Physiological and molecular metabolic consequences of fetal hyperglycernia

胎儿高血糖的生理和分子代谢后果

• 批准号: 10403005
• 负责人: Yann Gibert
• 金额: $ 24.42万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10403005
• 关键词: Adult; Atherosclerosis; Biological; Body mass index; Cardiovascular Diseases; Deposition; Development; Diabetes Mellitus; Diet; Disease; Embryo; Embryonic Development; Exposure to; Fatty acid glycerol esters; Fetal Death; Fetal Development; Fetal Macrosomia; Fetus; Glucose; Glycolysis; Goals; Health; Human; Hyperglycemia; Hyperlipidemia; Individual; Insulin Resistance; Life; Link; Lipids; Metabolic; Metabolic Diseases; Metabolic syndrome; Modeling; Molecular; Mothers; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Ovulation; Physiological; Research; Risk; System; Testing; Therapeutic Intervention; Yolk Sac; Zebrafish; fetal; fetal hyperglycemia; non-alcoholic fatty liver disease; oxidation; prevent

Fetal hyperglycemia occurs when the developing fetus is exposed to high levels of glucose. For example in humans, this is the case when the mother has diabetes. Fetal hyperglycemia is linked to health complications for the fetus, including preeclamsia, fetal macrosomia and even fetal death. In addition, fetal hyperglycemia also increases the risk for the individual to develop a variety of diseases later in life. Adults exposed to fetal hyperglycemia are more susceptible to obesity, insulin resistance, type 2 diabetes, cardiovascular diseases and several metabolic syndromes. To date, the physiological and molecular mechanisms that underlie the link between fetal hyperglycemia and the adult sequelae are poorly understood. The central goal of this project is to examine the physiological and molecular basis of metabolic diseases in adults exposed to high levels of glucose only during embryogenesis. To accomplish this goal, we have recently developed a zebrafish model of fetal hyperglycemia. Zebrafish offers several advantages to complete this project. From a biological point of view, zebrafish embryos have the unique feature of being a “closed system” i.e for the first 5 days of development, the embryo solely relies on the yolk sac reserved deposited by the mother during ovulation and no energy exchange happens with the exterior world prior the end of embryogenesis. Therefore, in zebrafish we can directly expose the embryos to known concentration of glucose. Thus, specific aim 1 will test the hypothesis that fetal hyperglycemia leads to an increase in BMI, fat mass and insulin resistance in adults fed normal diet. Specific aim 2 will test the hypothesis that embryonic hyperglycemia increases glycolysis while decreasing 􀈕-oxidation in embryos and in adults. Specific aim 3 will test the hypothesis that fetal hyperglycemia causes hyperlipidemia and non-alcoholic fatty liver disease in adults. Specific aim 4 will test the hypothesis that embryonic hyperglycemia increases the levels of circulating lipids and causes atherosclerosis later in life. Successful completion of this proposal will lead to a better understanding of the physiological and molecular consequences of fetal hyperglycemia and will help in defining strategic therapeutic interventions to prevent the development of metabolic diseases in adults exposed to glucose during embryogenesis.

当发育中的胎儿暴露于高水平的葡萄糖时，胎儿高血糖会发生。例如 在人类中，母亲患有糖尿病是这种情况。胎儿高血糖与健康有关 胎儿的并发症，包括前峰，胎儿大量症甚至胎儿死亡。此外， 胎儿高血糖还增加了个人以后生活中各种疾病的风险。 暴露于胎儿高血糖的成年人更容易受到肥胖，胰岛素抵抗，2型糖尿病的影响， 心血管疾病和几种代谢综合症。迄今为止，物理和分子 胎儿高血糖与成人后遗症之间联系的机制很差 理解齿。该项目的核心目标是检查的物理和分子基础 仅在胚胎发生过程中，成年人的代谢疾病仅在高水平的葡萄糖中。完成 这个目标，我们最近开发了斑马鱼的胎儿高血糖模型。斑马鱼提供了几种 完成该项目的优势。从生物学的角度来看，斑马鱼胚胎具有独特 作为开发前5天的“封闭系统”的特征，胚胎仅依赖于 母亲在排卵过程中保留的蛋黄囊保留了 胚胎发生结束之前的外部世界。因此，在斑马鱼中，我们可以直接暴露胚胎 已知的葡萄糖浓度。那是特定目标1将检验胎儿高血糖的假设 成人喂养正常饮食的BMI，脂肪质量和胰岛素抵抗的增加。具体目标2将 测试胚胎高血糖会增加糖酵解的假设，同时降低◎氧化 胚胎和成人。特定目标3将检验胎儿高血糖引起的假设 成人高脂血症和非酒精性脂肪肝病。具体目标4将检验以下假设 胚胎高血糖会增加循环脂质的水平，并在以后的生活中引起动脉粥样硬化。 成功完成这项建议将使人们更好地了解生理和 胎儿高血糖的分子后果，将有助于定义战略疗法 干预措施，以防止在成年人暴露于葡萄糖的成年人中发展的干预措施 胚胎发生。